Project Summary ? Project 2 Alcohol use disorder (AUD) imposes a substantial burden on society with far-reaching health consequences. The identification of novel genes and genetic pathways that influence alcohol-related behaviors will facilitate the development of new therapeutic interventions for AUD. In this project my laboratory will use the Drosophila (fruit fly) model to investigate genes and genetic pathways that have novel influences on ethanol-related behavior. Molecular-genetic information from this project should ultimately lead to better diagnosis, risk determination and treatment of AUD in humans. A major focus for this project will be to explore the role of the MADS-box transcription factor Mef2 family in ethanol-related behavior. Our preliminary studies implicate a MEF2 family member in the subjective response to ethanol (SRE) in humans and also show that the sole fly ortholog Mef2 is required for normal ethanol sedation. Our data suggest that altered ethanol sedation in humans might underlie changes in SRE and that changes in both sedation and SRE might be driven by genetic variance in MEF2 genes. Our results also support the hypothesis that a deeper understanding of the Mef2 family of genes could lead to important insights regarding behavioral responses to ethanol, SRE and potentially AUD. Another major focus of this project will be to continue using the fly as an experimental platform for investigating the role of other candidate genes in ethanol behavior prioritized by our Bioinformatics and Analysis Core and/or implicated by studies in other Center Projects. Given our success with studies on Clic, the ryanodine receptor and Mef2, we will further invest in this cross-species approach for exploring conserved genes and pathways underlying ethanol-related behaviors in flies and multiple aspects of alcohol abuse in humans.